Headache or No Headache, PFO-Related Auras Have Same Cause

Auras experienced by patients with patent foramen ovale (PFO) likely have similar etiologies whether or not they occur in patients who also experience migraine headaches, according to research published in the June 2012 issue of JACC: Cardiovascular Interventions. The study also suggests that closing the PFO will produce symptom relief, a finding that could be confirmed upon completion of an ongoing clinical trial.

Among patients referred to the University of California, Los Angeles (Los Angeles, CA) for suspected PFO, Jonathan M. Tobis, MD, and colleagues identified 225 who experienced visual aura with or without migraine headache. Participants were divided into 3 groups according to the occurrence of:

Aura associated with migraine headache (n = 175)

Aura unrelated in time to migraine headache (n = 29)

Aura but no migraine headache (n = 21)

The investigators next compared the frequency of right-to-left shunt on transcranial Doppler among the 3 groups, which were compared with a control group of 200 patients referred to the cardiac cath lab for diagnostic catheterization unrelated to PFO. Controls had neither migraine headache nor aura.

The frequency of shunting was highest among patients who experienced aura plus migraine and similar for those who experienced aura unrelated to migraine or without migraine. Together, all patients who experienced aura had much higher rates of shunting than controls (18%; P < 0.0001). Eighty patients (36%) underwent PFO closure, which resolved aura and/or migraine headache in most patients after 12 months irrespective of aura category (P = NS; table 1).

Table 1. Prevalence According to Aura Category

With Migraine

Unrelated in Time
to Migraine

Without Migraine

Presence of Right-to-Left Shunt

96%

72%

67%

Proportion of Shunts Closed

40%

38%

36%

Symptom Resolution After PFO Closure

52%

75%

80%

Abbreviation: PFO, patent foramen ovale.

Exploring the Connection

In a telephone interview with TCTMD, Robert J. Sommer, MD, of Columbia University Medical Center (New York, NY), explained why PFOs might be linked to migraines in the first place. “Perhaps patients who are capable of having embolic material cross from the right side to the left side through the PFO could have microembolization cross through without being large enough to cause strokes,” he said. “That would explain why closing the holes in some patients, for whom microembolization is the trigger [for migraine headaches], would potentially treat their headaches. It also explains why, in a number of patients with migraines, antiplatelet therapy can also reduce these patients’ headaches.”

For his part, Dr. Tobis believes the trigger is more likely to be a chemical than a particle, though the mechanism whereby the chemical passes through the shunt and lands in a vulnerable area of the brain would be the same.

“The migraine is very typical,” he told TCTMD in a telephone interview. “That is, the patient usually has the headache on the same side, and they have an aura of the same type. If it were a particle, it would land randomly so you’d have a [transient ischemic attack or] a stroke that would be very different each time. But migraines tend to be very stereotypic.”

Why Others Failed

Muddying the waters regarding the link between PFO and migraine is the MIST (Migraine Intervention with STARFlex Technology) trial, which did not reveal a benefit to PFO closure for migraine sufferers. But several factors could explain this finding, the physicians commented.

“Until we can predict which patients are going to benefit from closure, it’s very hard to set up a trial where we are isolating migraines as a sole endpoint,” said Dr. Sommer. “I think that’s why MIST failed, because we were taking all-comers. Down the road, hopefully we’ll have a way of choosing the right patients. For example, there are patients who have white matter lesions on their MRI. Nobody really knows what they are but they could represent microembolization.”

Dr. Tobis believes that the failure of both MIST and CLOSURE I, which found no benefit of PFO closure for secondary stroke risk, boils down to the device used, STARFlex (originally produced by the now-defunct NMT Medical). In October 2011, the company’s assets and intellectual property were purchased by WL Gore and Associates (Flagstaff, AZ). “I have been critical of that device because I thought it was thrombogenic and led to strokes,” he said. “Also, 15% of the cases did not close well. If anything, it opened up and increased the shunt. I think to a large extent that explains the negative results.”

While there is still no device specifically approved by the US Food and Drug Administration for PFO closure, those currently available for use in clinical trials and off-label are good, said Dr. Tobis.

Three ongoing trials, therefore, should help elucidate the true benefits of PFO closure. Notably, the RESPECT [Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment] and REDUCE trials are exploring the benefits of PFO closure for cryptogenic stroke using the HELEX Septal Occluder (Gore Medical) and the AMPLATZER PFO Occluder (AGA Medical, Minneapolis, MN), respectively. The PREMIUM [Prospective Randomized investigation to Evaluate the incidence of headache reduction in subjects with Migraine and PFO Using the AMPLATZER PFO Occluder compared to Medical Management] trial is assessing the ability of PFO closure to reduce severe, debilitating migraine.

Study Implications

“The implication [of this study] is that the etiology [of aura with and without headache] is probably the same,” said Dr. Tobis. “But it’s also multifactorial. Not all people with migraine have a PFO, so there are clearly other reasons for having migraines besides [right-to-left] shunting. And not everybody with a PFO has migraine, so there’s probably a brain structure that’s predisposed to migraine as well as precipitating events.”

Dr. Sommer stressed that chronic migraine patients should always be checked for shunting at the atrial level. “Tests like echocardiography with bubble contrast injection or transcranial Doppler can be an important part of identifying those patients. Even if we don’t know what the proper therapy is for those patients at this moment, by making the association, they could eventually be eligible for clinical trials, etc,” he concluded.

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